Exploring the Role of Water Molecules for Docking and Receptor Guided 3D-QSAR Analysis of Naphthyridine Derivatives as Spleen Tyrosine Kinase (Syk) Inhibitors

In the present study, 3D-QSAR analysis was performed utilizing docking based alignment of [1,6]-naphthyridine derivatives as Syk enzyme inhibitors. The role of the water molecules was explored for the docking based alignment that revealed two conserved water molecules important for proper orientation and alignment of naphthyridine inhibitors in the active site of Syk enzyme. The QSAR model was selected having highest value of Q(2) (0.624) and Pearson-r (0.862). The selected model also displayed the highest values of R(2) (0.978) and F-value (184.5) and the lowest SD (0.862). The contour plots developed on the basis of the best model helped to reveal the essential structural features of naphthyridines derivatives responsible for inhibition of Syk enzyme. The generated model and information revealed from it was utilized to design and predict new congeneric molecules that can be used as potential therapeutic agents.

[1]  Yu-Quan Wei,et al.  Pharmacophore modeling study based on known spleen tyrosine kinase inhibitors together with virtual screening for identifying novel inhibitors. , 2009, Bioorganic & medicinal chemistry letters.

[2]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.

[3]  K. Miyazawa,et al.  Structure-activity relationship studies of imidazo[1,2-c]pyrimidine derivatives as potent and orally effective Syk family kinases inhibitors. , 2008, Bioorganic & medicinal chemistry.

[4]  K. Miyazawa,et al.  A novel Syk family kinase inhibitor: design, synthesis, and structure-activity relationship of 1,2,4-triazolo[4,3-c]pyrimidine and 1,2,4-triazolo[1,5-c]pyrimidine derivatives. , 2008, Bioorganic & medicinal chemistry.

[5]  Valentino J Stella,et al.  Prodrugs of 2,4-pyrimidinediamine compounds and of their uses. , 2006 .

[6]  Woody Sherman,et al.  Analysis and comparison of 2D fingerprints: insights into database screening performance using eight fingerprint methods , 2010, J. Cheminformatics.

[7]  Om Silakari,et al.  Elaboration of New Anti-Inflammatory Agents Using Pharmacophore Based 3D QSAR of 4, 5-Diaryl Imidazoline as P2X7 Receptor Antagonists , 2012 .

[8]  Masaya Orita,et al.  Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives. , 2005, Bioorganic & medicinal chemistry.

[9]  David E. Shaw,et al.  PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results , 2006, J. Comput. Aided Mol. Des..

[10]  R. Geha,et al.  SLP-76 deficiency impairs signaling via the high-affinity IgE receptor in mast cells. , 1999, The Journal of clinical investigation.

[11]  G. Tsokos,et al.  Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases , 2010, Arthritis research & therapy.

[12]  싱 라진더,et al.  2,4-pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases , 2004 .

[13]  T. Yamamoto,et al.  Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling , 1994, The Journal of experimental medicine.

[14]  Thompson N. Doman,et al.  3D QSAR Methods: Phase and Catalyst Compared. , 2007 .

[15]  Jim W Barnett,et al.  Structural Insights for Design of Potent Spleen Tyrosine Kinase Inhibitors from Crystallographic Analysis of Three Inhibitor Complexes , 2009, Chemical biology & drug design.

[16]  Renee L DesJarlais,et al.  Discovery and SAR of novel Naphthyridines as potent inhibitors of spleen tyrosine kinase (SYK). , 2003, Bioorganic & medicinal chemistry letters.

[17]  David A. Evans,et al.  3D QSAR Methods: Phase and Catalyst Compared , 2007, J. Chem. Inf. Model..

[18]  E. Meltzer,et al.  An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. , 2005, The Journal of allergy and clinical immunology.

[19]  Stephen K Burley,et al.  A Novel Mode of Gleevec Binding Is Revealed by the Structure of Spleen Tyrosine Kinase* , 2004, Journal of Biological Chemistry.

[20]  Mohammed A. Kashem,et al.  Three Mechanistically Distinct Kinase Assays Compared: Measurement of Intrinsic ATPase Activity Identified the Most Comprehensive Set of ITK Inhibitors , 2007, Journal of biomolecular screening.

[21]  M. Bajpai,et al.  Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases. , 2009, IDrugs : the investigational drugs journal.

[22]  Jian Wang,et al.  Discovery and SAR of novel 4-thiazolyl-2-phenylaminopyrimidines as potent inhibitors of spleen tyrosine kinase (SYK). , 2008, Bioorganic & medicinal chemistry letters.

[23]  A. Tropsha,et al.  Beware of q2! , 2002, Journal of molecular graphics & modelling.

[24]  Charles L. Cywin.  Discovery and SAR of Novel [1,6]Naphthyridines as Potent Inhibitors of Spleen Tyrosine Kinase (SYK). , 2003 .

[25]  Feifei Zhao,et al.  Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor. , 2007, Clinical immunology.